1. Field of the Invention
The invention generally relates to agents and methods for releasing H2S in an aqueous environment. In particular, the invention provides agents of various formulations which release H2S in a controlled, predictable and sustained manner upon contact with an aqueous environment, such as the circulatory system of an animal, and which are thus suitable for in vivo delivery of H2S.
2. Background of the Invention
Hydrogen sulfide (H2S) is a noxious gas with the characteristic smell of rotten eggs. Recent studies recognized H2S as the third gaseous transmitter beside nitric oxide (NO) and carbon monoxide (CO) that influence various physiological processes. (Calvert 2010, Gadalla 2010, Szabo 2007, Lowicka 2007, Blackstone 2005) H2S has been shown to relax vascular smooth muscles, mediate neurotransmission, elicit hibernation, inhibit insulin signalling, regulate inflammation and blood vessel caliber. (Calvert 2010, Gadalla 2010, Szabo 2007, Lowicka 2007, Blackstone 2005) Endogenous formation of H2S is achieved by enzymes such as cystathionine-β-synthase (CBS) in the brain and cystathionine-γ-lyase (CSE) in liver, vascular and non-vascular smooth muscle. Although its exact chemical and biochemical modes of action are still not fully understood, levels of H2S in the brain and vasculature have unambiguously been associated with human health and disease. (Calvert 2010, Gadalla 2010, Szabo 2007, Lowicka 2007, Blackstone 2005)
To study the physiological and pathophysiological properties of H2S, the direct use of H2S gas or NaHS in aqueous solutions are typical. However, the therapeutic potential of H2S gas seems to be limited due to difficulties in obtaining precisely controlled concentrations and possible toxic impact of H2S excess. NaHS, although widely used as a research tool, is a short-lasting donor which does not mimic the slow and continuous process of H2S generation in vivo. In addition, NaHS in aqueous solution can be rapidly oxidized by O2. Modifications that are made between the time that a solution is prepared and the time that the biological effect is measured can dramatically affect results. Due to these limitations, H2S-releasing agents (i.e. H2S donors) are considered useful tools in the study of H2S. (Calvert 2010, Gadalla 2010, Szabo 2007, Lowicka 2007, Blackstone 2005, Caliendo 2010, Jacob 2008) However, currently available H2S donors are very limited. (Calvert 2010, Gadalla 2010, Szabo 2007, Lowicka 2007, Blackstone 2005, Caliendo 2010, Jacob 2008) Besides NaHS, only three types of H2S donors have been reported: 1) garlic-derived polysulfide compounds, such as diallyl trisulfide (DATS). H2S release from DATS was suggested to mediate the vasoactivity of garlic. (Benavides 2007) 2) GYY4137, a Lawesson's reagent derivative, is a synthetic H2S donor. This molecule decomposes spontaneously in aqueous buffers to release H2S. (Li 2009, Li 2008) 3) A dithiolthione moiety as a H2S donor has been used to prepare H2S— nonsteroidal anti-inflammatory drug hybrids like S-diclofenac. (Baskar 2008) In addition, biological thiols such as cysteine and glutathione can be H2S donors upon enzymatic or thermal treatment (Morra 1991). A limitation of these known donors is that H2S release is too fast to mimic biological H2S generation. Given the structural characters of these compounds, little can be done to modify their structures to control the release of H2S. Therefore, developing new H2S donors with controllable H2S generation capability is critical for this field. Ideal H2S donors, from a therapeutic point of view and for applications in H2S-related biological research, should release H2S slowly and in moderate amounts. (Caliendo 2010, Jacob 2008). There is a need for the development of chemical agents capable of controllably releasing H2S for use within biological systems.